Bone remodeling is controlled by two cell types, the osteoblast and the osteoclast, that regulate matrix deposition and mineral resorption, respectively. Together, these two cell types control bone growth, shape, mass and strength. The intricate balance between rates of deposition and resorption is a key element in the regulation of bone remodeling and systemic Ca+2 homeostasis, both of which impact directly on the mineralized tissues of the oral cavity. Preliminary data obtained using metabolites/analogs of 1,25(OH)2D3 indicates that there are at least two separate pathways for modulation of osteoblast function by the calcitropic hormone 1,25(OH)2D3 during bone growth and remodeling including both rapid-plasma membrane-mediated events as well as slower nuclear receptor-mediated events. 1-Deoxy analogs have been identified that bind very poorly to the nuclear receptor but can activate Ca+2 channels present in the plasma membrane of the osteoblast. OUR HYPOTHESIS IS THAT BOTH RAPID MEMBRANE EFFECTS AND LONG TERM GENE ACTIVATION ARE REQUIRED TO EXPLAIN THE EFFECTS OF 1,25(OH)2D3 ON BONE CELL FUNCTION. This proposal outlines a variety of biochemical, pharmacological, electrophysiological, ion flux, and molecular biological approaches designed to dissect the regulation of osteoblast function by 1,25(OH)2D3.